Submissions for variant NM_002180.3(IGHMBP2):c.1060+8G>T

gnomAD frequency: 0.00076  dbSNP: rs201147313

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725441	SCV000336957	uncertain significance	not provided	2015-11-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000398567	SCV000373773	uncertain significance	Autosomal recessive distal spinal muscular atrophy 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000341120	SCV000519004	likely benign	not specified	2018-01-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV001080208	SCV000642293	likely benign	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2024-01-29	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001174191	SCV001337317	likely benign	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000725441	SCV001472841	likely benign	not provided	2020-04-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725441	SCV001500978	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000341120	SCV002500218	likely benign	not specified	2022-03-08	criteria provided, single submitter	clinical testing	Variant summary: IGHMBP2 c.1060+8G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant no significant impact on splicing. Three predict the variant creates an alternate intronic 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0006 in 251294 control chromosomes. This frequency does not allow conclusions about variant significance. To our knowledge, no occurrence of c.1060+8G>T in individuals affected with Charcot-Marie-Tooth Disease, Axonal, Type 2S and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.